SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Diflunisal 250 mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 250 mg of the active ingredient, diflunisal.

3    PHARMACEUTICAL FORM

Peach-coloured, capsule-shaped, film-coated tablets, marked ‘MSD 675’.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Diflunisal is indicated in the relief of pain.

Diflunisal is also indicated in the relief of pain and inflammation associated with osteoarthritis and rheumatoid arthritis.

Diflunisal is also indicated in the relief of pain and associated symptoms of primary dysmenorrhoea.

4.2 Posology and method of administration

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

For oral administration.

Tablets should be swallowed whole, not crushed or chewed and taken preferably with or after food. Food does not have a clinically significant effect on the rate and extent of diflunisal absorption.

It is prudent to start at the bottom end of the dose range. In certain cases, it will be necessary to start with a high initial dose, as described in the dosage recommendations below.

For relief of pain

An initial dose of 1,000 mg, followed by 500 mg every 12 hours, is recommended for most patients. Following the initial dose, some patients may require 500 mg every eight hours.

Maintenance doses higher than 1,500 mg a day are not recommended.

For osteoarthritis and rheumatoid arthritis

The recommended dosage range is 500 mg to 1,000 mg per day. Diflunisal may be administered once or twice a day.

Dosage should be adjusted to the nature and intensity of the pain being treated. For dysmenorrhoea

The recommended dosage is 1,000 mg at the onset of cramps or bleeding, followed by 500 mg every 12 hours for as long as symptoms last, usually a maximum of five days.

Use in children: Diflunisal is not recommended for children.

Use in the elderly: The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

4.3 Contraindications

Hypersensitivity to any component of this product.

Severe heart failure.

In patients who have previously experienced acute asthmatic attacks, urticaria, rhinitis or angioedema precipitated by ibuprofen, aspirin or non-steroidal anti-inflammatory drugs (NSAIDs).

The drug should not be administered to patients with a history of, or active gastro-intestinal bleeding or perforation related to previous NSAIDs therapy.

NSAIDs, including diflunisal, should not be given to patients with active or previous peptic ulceration.

Diflunisal is contra-indicated during the third trimester of pregnancy and in breast-feeding mothers (see 4.6 ‘Pregnancy and lactation’).

Severe hepatic failure and, renal failure (see 4.4 ‘Special warnings and precautions for use’.)

4.4 Special warnings and precautions for use

Undesirable effects may be minimized by using the minimum effective dose for the shortest duration necessary to control symptoms (see section 4.2 and GI and cardiovascular risks below).

Elderly:

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see Section 4.2 ‘Posology and administration’).

Infections

NSAIDs, including diflunisal, may mask the usual signs and symptoms of infection. Therefore, the physician must be continually on the alert for this and should use the drug with extra care in the presence of existing infection.

Concomitant medications

Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin or anti-platelet agents such as aspirin (see section 4.5 ‘Interaction with other medicinal products and other forms of interaction’).

The use of diflunisal with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see Section 4.5 ‘Interactions’).

Platelet aggregation

Although diflunisal has less effect on platelet function and bleeding time than aspirin, at higher doses it is an inhibitor of platelet function; therefore, patients who may be adversely affected should be carefully observed when diflunisal is administered.

Ocular effects

Because of reports of adverse eye findings with agents of this class, it is recommended that patients who develop eye complaints during treatment with diflunisal have ophthalmological evaluations.

Gastro-intestinal effects

Diflunisal should be used with caution in patients having a history of gastro-intestinal haemorrhage, ulcers, ulcerative colitis or Crohn’s disease.

Gastro-intestinal bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. If gastrointestinal bleeding or ulceration occurs, the treatment should be withdrawn. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding).

In patients with a history of peptic-ulcer disease and in the elderly, NSAIDs should be given only after other forms of treatment have been carefully considered.

Respiratory effects

Diflunisal should be used with caution in patients suffering from, or with a previous history of bronchial asthma. NSAIDs have been reported to precipitate bronchospasm in some patients.

Reye ’s syndrome

Although there have been no known reports associated with the use of diflunisal to date, acetyl salicylic acid has been associated with Reye’s syndrome. Because diflunisal is a compound related to salicylic acid, the possibility of an association with Reye’s syndrome cannot be excluded.

Renal effects

As with other NSAIDs, there have been reports of acute interstitial nephritis with haematuria, proteinuria, and occasionally nephrotic syndrome in patients receiving diflunisal.

In patients with reduced renal blood flow where renal prostaglandins play a major role in maintaining renal perfusion, administration of a NSAID may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with renal or hepatic dysfunction, diabetes mellitus, advanced age, extracellular volume depletion, congestive heart failure, sepsis, or concomitant use of any nephrotoxic drug. An NSAID should be given with caution and renal function should be monitored in any patient who may have reduced renal reserve. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Since diflunisal is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored; a lower daily dosage should be used to avoid excessive drug accumulation. In patients with severe renal impairment, the drug should not be used.

In rats and dogs, high oral doses of diflunisal (50 to 200 mg/kg/day), as with aspirin, produced similar pathological changes (gastro-intestinal ulceration and renal papillary oedema). These dosages are approximately 3 to 12 times the maximum dosages recommended in man.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDS (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events ( for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for diflunisal.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diflunisal after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (eg hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Hypersensitivity syndrome

A potentially life-threatening, apparent hypersensitivity syndrome has been reported. In cases where this syndrome is suspected, therapy should be discontinued immediately and not reinstituted. This multisystem syndrome includes constitutional symptoms (fever, chills), and cutaneous findings (see 4.8 ‘Undesirable effects’, Dermatological). It may also include involvement of major organs (changes in liver function), jaundice, leucopenia, thrombocytopenia, eosinophilia, disseminated intravascular coagulation, renal impairment (including renal failure), and less specific findings (adenitis, arthralgia, myalgia, arthritis, malaise, anorexia, disorientation).

Laboratory tests

AST (SGOT) and ALT (SGPT) levels rose significantly by three times the upper limit of normal in less than 1% of patients in controlled clinical trials of NSAIDs.

Hepatic effects

A patient on diflunisal with signs or symptoms suggesting liver disease, or in whom abnormal liver-function tests have occurred, should be evaluated for evidence of a more severe hepatic reaction. If abnormal liver tests persist or worsen, if signs or symptoms of liver disease develop, or if systemic manifestations such as eosinophilia or rash occur, diflunisal should be discontinued.

Female fertility:

The use of diflunisal may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation in infertility, withdrawal of diflunisal should be considered.

4.5 Interaction with other medicinal products and other forms of interaction

Indomethacin: The combined use of indomethacin and diflunisal has been associated with fatal gastro-intestinal haemorrhage. The combination should not be used. Co-administration of diflunisal with indomethacin increases the plasma level of indomethacin by about 30 to 35% with a concomitant decrease in renal clearance of indomethacin and its conjugate.

Other NSAIDs: The concomitant use of diflunisal and other NSAIDs (including cyclooxygenase-2 selective inhibitors) is not recommended owing to the increased possibility of gastro-intestinal toxicity, with little or no increase in efficacy.

Aspirin: Co-administration of aspirin causes approximately a 15% decrease in plasma levels of diflunisal.

Naproxen: Normal volunteers given naproxen and diflunisal showed no changes in plasma levels of either drug, but a significant decrease in urinary excretion of naproxen and its glucuronide metabolite.

Sulindac: Normal volunteers given sulindac and diflunisal showed substantial but not statistically significant lower levels of the active sulphide metabolite of sulindac.

Paracetamol: Co-administration significantly increased the plasma levels of paracetamol by approximately 50% but the plasma levels of diflunisal were unaffected. Since paracetamol in high doses has been associated with hepatotoxicity, administration of diflunisal and paracetamol should be used cautiously, with careful monitoring of patients.

Gold salts: In clinical studies of patients with rheumatoid arthritis, diflunisal added to the regimen of gold salts usually resulted in additional symptomatic relief.

Codeine: Co-administration with diflunisal improves the analgesic efficacy of either drug taken alone.

Methotrexate: Caution should be used if diflunisal is administered concomitantly with methotrexate. NSAIDs    have been    reported to

decrease the tubular secretion of methotrexate and potentiate the toxicity.

Ciclosporin: Administration of NSAIDs concomitantly with ciclosporin has been associated with an increase in ciclosporin-induced toxicity, possibly due to decreased synthesis of renal prostaciclin. NSAIDs should be used with caution in patients taking ciclosporin, and renal function should be monitored carefully.

Oral anticoagulant drugs: The concomitant administration of diflunisal and warfarin or nicoumalone resulted in prolongation of prothrombin time in normal volunteers. This may occur because diflunisal competitively displaces coumarins from protein binding sites. Accordingly, prothrombin time should be monitored during, and for several days after, the concomitant drug administration of diflunisal and oral anticoagulants. The dosage of oral anticoagulants may require adjustment.

Antihypertensives',    the antihypertensive effects of some antihypertensive

agents including ACE inhibitors, beta-blocking agents and diuretics, may be reduced when used concomitantly with NSAIDs. Caution should therefore be exercised when considering the addition of NSAID therapy to the regimen of a patient taking antihypertensives therapy.

Cardiac glycosides: an increase in serum-digoxin concentration has been reported with concomitant use of aspirin, indomethacin and other NSAIDs. Therefore when concomitant digoxin and NSAID therapy is initiated or discontinued, serum-digoxin levels should be closely monitored.

Diuretics

NSAIDs may reduce the effect of diuretics. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Lithium: concomitant use of indomethacin with lithium, produced a clinically relevant elevation of plasma lithium and reduction in renal lithium clearance in psychiatric patients and normal subjects with steady-state plasma lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis and the potential exists for a similar effect with other NSAIDs.

As a consequence, when an NSAID and lithium are given concomitantly, the patient should be observed carefully for signs of lithium toxicity. In addition the frequency of monitoring serum lithium concentrations should be increased at the outset of such combination therapy.

Corticosteroids:    the risk of gastro-intestinal bleeding and ulceration

associated with NSAIDs is increased when used with corticosteroids.

Mifepristone: NSAIDs and aspirin should be avoided until at least 8 to 12 days after administration of mifepristone.

Quinolone antibiotics: there have been reports that 4-quinolones may induce convulsions, in patients with or without a history of convulsions. Taking NSAIDs at the same time may also induce them.

Tolbutamide: No significant changes occurred in the plasma levels of tolbutamide or in the fasting blood sugar levels of diabetic patients who also took diflunisal.

Hydrochlorothiazide: Co-administration increases the plasma levels of hydrochlorothiazide by 25 to 35% with a concomitant decrease in renal clearance of the diuretic. This change is not clinically important. Diflunisal counteracts the hyperuricaemic effect of hydrochlorothiazide.

Frusemide: Co-administration did not affect the diuretic activity of frusemide in normal volunteers, but its hyperuricaemic activity was decreased by diflunisal.

Antacids: The clinical effect of occasional doses of antacid is insignificant, but this becomes significant when antacids are used continuously. Co-administration of aluminium hydroxide suspension significantly decreases the absorption of diflunisal by approximately 40%.

Drug/laboratory test interactions: Serum salicylate assays: Caution should be used in interpreting the results of serum salicylate assays when diflunisal is present. Because of the cross-reactivity between the two compounds, salicylate levels have been found to be falsely elevated with some assay methods.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding.

4.6 Pregnancy and lactation

NSAIDs should not be used during the first two trimesters of pregnancy unless the potential benefit to the patient outweighs the potential risk to the foetus. Use of diflunisal during the third trimester of pregnancy is contraindicated. The known effects of drugs of this class on the human foetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus post-natally which may be resistant to medical management; myocardial degenerative changes; platelet dysfunction with resultant bleeding; intracranial bleeding, renal dysfunction or failure; renal injury/dysgenesis which may result in prolonged or permanent renal failure; oligohydramnios; gastro-intestinal bleeding or perforation; and increased risk of necrotising enterocolitis.

See section 4.4 ‘Special warnings and precautions for use’ regarding female fertility.

Breast-feeding mothers should not take diflunisal, or should stop breastfeeding.

4.7 Effects on ability to drive and use machines

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

3% to 9% incidence

Gastro intestinal: gastro intestinal pain, dyspepsia, diarrhoea, nausea. Dermatological: rash.

Central nervous system: headache.

1% to 3% incidence

Gastro intestinal: vomiting, constipation, flatulence.

Central nervous system/psychiatric: dizziness, somnolence, insomnia. Special senses: tinnitus.

Miscellaneous: fatigue.

Less than 1 % incidence

Gastro intestinal: peptic ulcer, gastro intestinal perforation and bleeding sometimes fatal, particularly in the elderly, have been reported, anorexia, gastritis, haematemisis, melaena, ulcerative stomatitis. Exacerbation of colitis and Crohn’s disease (see Section 4.4 ‘Special warnings and precautions for use’) have been reported following administration.

Hepatic: jaundice, cholestasis, liver-function abnormality, hepatitis.

Dermatological: pruritus, sweating, dry mucous membranes, stomatitis, photosensitivity, urticaria, erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis.

Genito urinary: dysuria, renal impairment including renal failure, interstitial nephritis, haematuria, nephritic syndrome.

Central nervous system/psychiatric: vertigo, light headedness, paraesthesiae, nervousness, depression, hallucinations, confusion.

Haematological: thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia.

Special senses: transient visual disturbances including blurred vision.

Miscellaneous: asthenia, oedema.

Hypersensitivity reactions: acute anaphylactic reaction with bronchospasm, angioedema, hypersensitivity vasculitis, hypersensitivity syndrome (see 4.4 ‘Special warnings and precautions for use’).

Causal relationship unknown

Other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, the following observations are listed to serve as alerting information to physicians.

Respiratory: dyspnoea.

Cardiovascular and cerebrovascular: palpitations, syncope.

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of some NSAIDS (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events ( for example myocardial infarction or stroke) (see section 4.4).

Musculoskeletal: muscle cramps.

Miscellaneous chest pain, fulminant necrotising fasciitis, particularly in association with Group A haemolytic streptococcus (see 4.4 ‘Special warnings and precautions for use’).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Cases of overdosage have occurred and fatalities have been reported. The most common signs and symptoms observed with overdosage were drowsiness, dizziness, vomiting, nausea, epigastric pain, gastro-intestinal bleeding, diarrhoea, hyperventilation, tachycardia, sweating, tinnitus, disorientation, stupor, excitation and coma. Diminished urine output and cardiorespiratory arrest have also been reported. The lowest dose of diflunisal alone at which death was reported was 15 g; death has been reported from a mixed drug overdose that included 7.5 g diflunisal.

In the event of recent overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be observed carefully and given symptomatic and supportive treatment.

To facilitate urinary elimination of the drug, attempt to maintain renal function. Because of the high degree of protein binding, haemodialysis is not recommended. Monitor renal, liver function and patients clinical condition. Frequent or prolonged convulsions should be treated with intravenous diazepam.

The initial plasma half-life following single oral doses of diflunisal seems to be dose dependent, ranging from approximately 7.5 hours for a 250 mg dose to 11 hours for a 500 mg dose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Diflunisal in man has been shown to possess analgesic activity lasting up to 12 hours or more. In clinical trials, diflunisal produced highly effective levels of analgesia when administered twice a day.

As an inhibitor of prostaglandin synthetase, diflunisal has a dose-related effect on platelet function. In normal volunteers given diflunisal twice a day for eight days at doses within the recommended range 500-1,000 mg daily, 500 mg daily had no effect on platelet function and 1,000 mg daily had a slight effect. However, at 2,000 mg daily, which exceeds the maximum recommended dosage, diflunisal inhibited platelet function. In contrast to aspirin, these effects of diflunisal were reversible.

A loading dose of 1,000 mg provides faster onset of pain relief, shorter time to peak analgesic effect, and greater peak analgesic effects than an initial 500 mg dose.

Diflunisal at 1,000 mg twice daily (NOTE: exceeds the recommended dosage) causes a statistically significant increase in faecal blood loss, but this increase was only one-half as large as that associated with aspirin 1,300 mg twice daily.

5.2 Pharmacokinetic properties

Diflunisal is rapidly and completely absorbed following oral administration with peak plasma concentrations occurring between two and three hours. The drug is excreted in the urine as two soluble glucuronide conjugates accounting for about 90% of the administered dose. Little or no diflunisal is excreted in the faeces. As diflunisal is excreted primarily by the kidney, the greater the degree of renal impairment, the slower the plasma disappearance rate of the drug and its glucuronides. Diflunisal appears in human milk in concentrations of 2 to 7% of those in plasma. More than 99% of diflunisal in plasma is bound to proteins.

The plasma half-life of diflunisal is 8 to 12 hours. Because of this long halflife and non-linear pharmacokinetics, several days are required for diflunisal plasma levels to reach steady state following multiple doses. For this reason, an initial loading dose is necessary to shorten the time to reach steady-state levels, and two to three days of observation are necessary for evaluating changes in treatment regimens if a loading dose is not used.

5.3 Preclinical safety data

There are no pre-clinical data of relevance which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Cellulose, microcrystalline E460 Hydroxypropylcellulose E463 Magnesium stearate E572 Pregelatinised maize starch Sunset yellow aluminum lake E110 Talc

Titanium dioxide E171 Methylhydroxypropylcellulose E464 Carnauba wax E903.

6.2 Incompatibilities

None

6.3 Shelf life

HDPE Bottles 60 months

PVC Blister packs of 60 tablets: 36 months

6.4    Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5    Nature and contents of container

Packs of 50 tablets containing five PVC blister strips of 10 tablets, to give a total of 50 tablets.

Packs of 60 tablets containing six PVC blister strips of 10 tablets, to give a total of 60 tablets.

HDPE bottles with tamper-evident closures containing 100 tablets.

HDPE bottles with securitainer containing 1000 tablets.

6.6    Special precautions for disposal

None

7    MARKETING AUTHORISATION HOLDER

Chemidex Pharma Limited t/a Essential Generics

7 Egham Business Village

Crabtree Road

Egham

Surrey

TW20 8RB

8    MARKETING AUTHORISATION NUMBER(S)

PL 17736/0124

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29 September 1977/21 October 2008

10    DATE OF REVISION OF THE TEXT

15/10/2015